The Influence of Depression On The Progression of HIV: Direct and Indirect Effects

425231
5231Schuster et al.Behavior Modification

BMO36210.1177/014544551142
Behavior Modification
The Influence 36(2) 123–145

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DOI: 10.1177/0145445511425231
the Progression http://bmo.sagepub.com
of HIV: Direct and

Indirect Effects
Randi Schuster1, Marina Bornovalova2,

and Elizabeth Hunt2
Abstract
The authors suggest a theoretical model of pathways of HIV progression,
with a focus on the contributions of depression—as well as secondary, behav-
ioral and emotional variables. Literature was reviewed regarding (a) comor-
bid depression and the direct physiological effects on HIV progression and
(b) intermediary factors between HIV and disease progression. Intermedi-
ary factors included (a) substance use, (b) social support, (c) hopelessness,
(d) medication nonadherence, and (e) risky sexual behavior and the con-
traction of secondary infections. The authors suggest direct physiological
pathways from depression to HIV progression and indirect pathways (e.g.,
behavioral, social, and psychological). In addition to depression, substance use,
poor social support, hopelessness, medication nonadherence, and risky sexual
behavior seem to be integral in HIV progression. Based on the individual rela-
tionships of these variables to depression and HIV progression, a comprehen-
sive multipath model, incorporating all factors, serves to explain how severe
emotional distress may lead to accelerated progression to AIDS.
1
University of Illinois at Chicago, USA
2
University of South Florida, Tampa, USA
Corresponding Author:
Randi Schuster, Department of Psychology, University of Illinois at Chicago,
1007 W. Harrison St., Chicago, IL 60607, USA
Email: rschus2@uic.edu
Downloaded from bmo.sagepub.com at The University of Iowa Libraries on May 29, 2015
124 Behavior Modification 36(2)
Keywords
disease progression, HIV, mental health
Centers for Disease Control and Prevention data suggest that the total
number of people living with HIV in the United States has steadily increased
in recent years (HIV Surveillance Report: Diagnoses of HIV infection and
AIDS in the United States and dependent areas, 2009). The most recent
reports estimate that more than 1 million people in the United States are
currently infected (Centers for Disease Control, 2008), and 56,000 more
contract HIV infection each year (Hall et al., 2008). New treatments that are
more effective and manageable have allowed individuals to enjoy longer and
healthier lives than in the earlier decades, transforming HIV from a terminal
illness to a chronic disease. Nonetheless, HIV-positive Americans still face
multiple stressors, including stigmatization (Fishman, Lyketsos, & Treisman,
1996), diminished social support (Greene, Frey, & Darlega, 2002), increased
exposure to violence (Cohen et al., 2000; Vlahov et al., 1998), HIV-status
disclosure concerns (Rodkjaer, Sodermann, Ostergaard, & Lomborg, 2011),
and persistent HIV-associated neurocognitive deficits (Gonzalez et al., 2008;
Heaton et al., 1995; Heaton et al., 2011; Martin et al., 1992). As such, it is
not surprising that rates of current and lifetime major depression among
HIV-infected persons are higher (36% and 50%, respectively) than in the
general population (Asch et al., 2003; Atkinson & Grant, 1994; Dew et al.,
1997; Perkins et al., 1994; Rabkin, 1996).
The links between depression and prognostic indicators of HIV disease
progression as well as the behavioral factors implicated in HIV disease course
have been the subject of several prior reviews. Collectively, they document that
before and after the advent of highly active antiretroviral therapies (HAART),
depression exerts a putative influence on parameters of immune functioning,
resulting in increased morbidity, mortality, and progression of HIV infection
(Leserman, 2008; Whetten, Reif, Whetten, & Murphy-McMillan, 2008).
Furthermore, reviews of years of published investigations have shown that
depression influences HIV pathogenesis via modulation of neuroendocrine
biomarkers (Cole, 2008) and that remediation of psychological disturbance
through psychosocial interventions results in the improvement of immune
dysfunction (Carrico & Antoni, 2008). Indeed, co-occurring depression has
been shown to complicate the medical treatment of HIV, resulting in acceler-
ated immunosuppression as indexed by increased viral load and fluctuations
of CD4 lymphocyte count. It can also lower medication adherence and thus
Schuster et al. 125
jeopardize optimal treatment effect. Longitudinal studies suggest that chronic

depression, by suppressing the immune system, increases mortality in HIV-
positive individuals, even when controlling for medication use (Cook et al.,
2004; Ickovics et al., 2001; Ironson, O’Cleirigh, et al., 2005). Such findings
support the direct impact of major depression on HIV progression.
However, researchers have yet to formulate a comprehensive model to
explain this phenomenon. The connection between depression and HIV pro-
gression likely involves the interaction of various biological, behavioral, and
environmental variables. Although this review begins by describing the direct
physiological pathway from depression to immunosuppression, the primary
focus is on proximal factors connecting depression to HIV progression. We
argue that untreated depression leads to behavioral and psychological risk fac-
tors, resulting in a faster disease progression as measured by immunologi-
cal markers. We conclude by providing a comprehensive theoretical model
that incorporates variables from these two spheres.
Direct Consequences of Depression:

Psychoneuroimmunological Pathways
Studies document that symptoms of depression are associated with hormonal
abnormalities, including disturbances in levels of dehydroepiandrosterone,
(DHEA) norepinephrine, and corticosteroids (i.e., glucocorticoids). Notably,
most research examining factors contributing to HIV disease progression (i.e.,
increased viral load and/or CD4 counts) focuses on glucocorticoids, mea-
sured by levels of plasma or urinary cortisol. Thus, we focus on the contribu-
tions of depression—as well as secondary, behavioral and emotional variables
on enhanced cortisol secretion—and review the pathways via this one mecha-
nism in detail. Future investigations should consider additional behavioral and
biochemical pathways between depression and HIV progression.
It is important to briefly summarize the concept of allostatic load (AL),
which is a useful framework when considering physiological dysregulation and
the impact of such dysregulation on negative health outcomes. AL has tradi-
tionally been used to refer to the cumulative effects of environmental stress
on fluctuating levels of neuroendocrine markers. AL is mediated by a number
of interrelated systems, including the hypothalamic–pituitary–adrenal (HPA)
axis. This review will focus on some of the downstream neuroendocrine
effects of a dysregulated HPA axis, given that this physiological “stress
system” has been found to be particularly overactive in depressed individuals.
Again, the aim of this article is not to be a comprehensive review of the
physiological mechanisms through which stress, including depression, leads to

poor HIV outcomes. Activation of the HPA axis involves a cascade of hor-
mone reactions, beginning with the release of corticotrophin-releasing hor-
mone from the hypothalamus, followed by the release of adrenocorticotropic
hormone (ACTH) by the pituitary. Stimulated by ACTH, the adrenal cortices
produce and release glucocorticoids (cortisol). As such, this article will briefly
review how depression is linked with CD4 decline via abnormally elevated
cortisol, one physiological mechanism among many that might tie depression
with HIV progression.
Major depression—along with its diagnostic criteria (e.g., disturbances in
appetite, sleep patterns, and energy level)—results in overactivation of the HPA
axis (Chrousos & Gold, 1992; Pariante & Lightman, 2008). This hyperactiva-
tion results in excessive secretion and inhibited regulation of glucocorticoids.
The elevated level of circulating glucocorticoids compromises some of the pri-
mary mechanisms in the immunologic response (e.g., granulocytic cells and
monocytes) against antigens. The immunosuppressive effects of excessive glu-
cocorticoids include inducing cell death and removal of T cells from circulation
via the interruption of lymphocyte production in the thymus (Meuleman &
Katz, 1985). Excessive glucocorticoids also affect the release of interleukins
and interferons, which inhibits the ability of lymphocytes to respond to an
infectious agent. Finally, studies have shown that glucocorticoids enhance HIV
replication (Goodkin et al., 1996; Markham, Salahuddin, Veren, Orndorff, &
Gallo, 1986). As an additional problem, depression leads to blunted produc-
tion and activity of cytotoxic lymphocytes, specifically natural-killer (NK)
cells (Herbert & Cohen, 1993; Kronfol et al., 1989) and an elevation of
inflammatory cytokines (Maes et al., 1993; Maes et al., 1995), thereby dis-
turbing immune response.
The pathway from depression to HPA hyperactivation to inhibited lym-
phocyte activity is especially relevant to HIV-positive individuals given that
elevated cortisol levels may result in compromised immune functioning (gen-
erally indexed via CD4 and T-cell counts) and subsequent disease progression.
For this population, elevated cortisol levels result in an altered T-lymphocyte
production of cytokines, triggering T-cell destruction and thereby resulting
in increased viral replication (Clerici et al., 1997; Corley, 1996). Petitto and
colleagues (2000) found that among HIV-positive men, basal cortisol levels
were associated with measures of immune functioning, including NK lym-
phocytes and T lymphocytes. Leserman and colleagues (2000, 2002) found
that increased cortisol was related to markers of disease progression—AIDS
(CD4 count < 200 or presence of an opportunistic infection uncommon in the
general population, including certain types of tuberculosis), clinical AIDS
Schuster et al. 127
condition (both criteria present), and mortality. In sum, evidence suggests that
elevated cortisol likely plays a primary role in the link between depression and
HIV progression.
Intermediary Factors Directly or Indirectly

Leading to Elevated Cortisol Levels
Depression → Substance Use → HIV Progression
There is a clear association between HIV serostatus, depression, and substance
use. The HIV Cost and Services Utilization Study, a large national study of
HIV-infected individuals receiving medical care, documented elevated rates
for substance abuse and co-occurring disorders compared with the general
population (Galvan, Burnam, & Bing, 2003). Among HIV-positive individu-
als with substance use disorders, depression is well documented (Berger-
Greenstein et al., 2007; Bouhnik et al., 2005; Rabkin et al., 1997). Studies
report that HIV-positive substance users are more likely to report elevated
symptoms of depression compared with HIV-positive individuals not using
drugs/alcohol (Cook et al., 2007; McClure, Catz, Prejean, Brantley, & Jones,
1996). Thus, there is evidence for three-way associations between depression,
substance use, and HIV serostatus.
Among the problems substance abuse presents for HIV-positive persons
is elevated cortisol levels caused by alcohol/drugs (Sipp, Blank, Lee, &
Meadows, 1993; Tabakoff, Jafee, & Ritzmann, 1978). This, as noted above,
is linked with immunosuppression. Studies have found that alcohol consump-
tion increases replication of HIV-1 and decreases cytokines, T-helper cells,
and T-suppressor cells (Bagasra, Kajdacsy-Balla, Lischner, & Pomerantz,
1993; Crum, Galai, Cohn, Celentano, & Vlahov, 1996). These molecular
changes accelerate the progression from HIV to AIDS (Balla, Lischner,
Pomerantz, & Bagasra, 1994). In addition, Pol, Artru, Thépot, Berthelot, and
Nalpas (1996) reported that substance use cessation is associated with
significant improvement in immune functioning and general health among
HIV-positive individuals.
Deterioration in HIV status may also occur as a secondary consequence of
heavy substance use. Examples of this include alcohol-exacerbated liver tox-
icity (Dingle & Oei, 1997), impaired metabolism of antiretroviral medications
(Kresina et al., 2002), and reduced treatment adherence (Eldred, Wu, Chaisson,
& Moore, 1998; Samet, Horton, Meli, Freedberg, & Palepu, 2004). Finally, the
compromised immune functioning secondary to substance use may make
HIV-infected individuals more prone to contracting new infections such as
Hepatitis B (Page-Shafer, Delorenze, Satariano, & Winkelstein, 1996). This results

in further immunosuppression for this at-risk population.
Depression → Poor Social Support →HIV Progression

Depression and social isolation are strongly linked and exert reciprocal influ-
ences cross-sectionally and over time (Joiner, 1999). Depression leads to poorer
quality of social support in healthy (Davila, Bradbury, Cohan, & Tochluk, 1997)
and HIV-infected populations (Kelly et al., 1993; McClure et al., 1996;
Song & Ingram, 2002). Conversely, low social support increases depression
and predicts depression chronicity (Brugha et al., 1990; Joiner, Katz, & Lew,
1997; Lara, Leader, & Klein, 1997). Theoretical work suggests that depression
erodes social support, resulting in disengaging from one’s social network,
actively soliciting criticism, avoiding self-assertion, and seeking repeated assur-
ances of self-worth and lovability from loved ones (Joiner, 1999).
The degree of social support strongly influences immune functioning in
the general population. Low social support is inherently stressful and linked
to higher baseline cortisol in both experimental studies (Kirschbaum, Klauer,
Filipp, & Hellhammer, 1995; Sayal et al., 2002; Uchino, Cacioppo, & Kiecolt-
Glaser, 1996) and associational studies (Heinrichs, Baumgartner, Kirschbaum,
& Ehlert, 2003; Turner-Cobb, Sephton, Koopman, Blake-Mortimer, & Spiegel,
2000). Among HIV-positive samples, low social support is correlated with ele-
vated cortisol over time (Leserman et al., 2002), as is the loss of social support
through death of significant others (Goodkin et al., 1998).
Lack of social support in this population is also a risk factor for faster
decline in CD4 lymphocyte counts (Leserman et al., 1999; Leserman et al.,
2000; Leserman et al., 2002; Solano et al., 1993). Fewer social resources
result in shorter life expectancy and a worsening of various infectious dis-
eases (House, Landis, & Umberson, 1988). Leserman et al. (1999) found that,
at 5-year follow-up, the probability of progressing to AIDS was about 2.5 times
higher among individuals with below-average social support. In another pro-
spective study, social support was not related to CD4 counts but predicted a
slower decline in CD4 counts and longer survival (Theorell et al., 1995).
Social support influences immune function through a number of lifestyle vari-
ables as well, including drug/alcohol use, medication adherence, and general
health behaviors (Ironson et al., 1994; Simoni, Frick, & Huang, 2006; Webb,
Vanable, Carey, & Blair, 2007), although the correlation between social support
and immune functioning remains significant even when controlling for these
factors (Theorell, Orth-Gomér, & Eneroth, 1990; Thomas, Goodwin, & Goodwin,
1985). For example, studies suggest a relationship between substance use
Schuster et al. 129
severity and social support. Perceived social support and a large social network
were negatively correlated with substance abuse among incarcerated women
(Staton-Tindall, Royse, & Leukfeld, 2007). Among HIV-positive individuals,
Webb and colleagues (Webb et al., 2007) found that heavy smokers perceived
less social support than other participants. Research has also demonstrated the
relationship between social support and medication adherence in this popu-
lation (Catz, Kelly, Bogart, Benotsch, & McAuliffe, 2000; Gordillo, del Amo,
Soriano, & González-Lahoz, 1999). In sum, decreased social support among
depressed individuals, may compromise immune functioning, both directly as
well as through intermediary behavioral mechanisms.
Depression → Hopelessness → HIV Progression

Hopelessness, defined as recurring negative expectations about one’s self and
the future (McLaughlin, Miller, & Warwick, 1996; Scheier & Carver, 1992), is
a frequent component of depression (Abramson, Metalsky, & Alloy, 1989;
Kazdin, French, Unis, Esveldt-Dawson, & Sherick, 1983; Kovacs, Beck, &
Weissman, 1975). Moderate to severe hopelessness is common among indi-
viduals with comorbid depression and HIV (Catalan et al., 1992; Ironson,
Balbin, et al., 2005; Rabkin, Williams, Neugebauer, Remien, & Goetz, 1990).
Cross-sectional and longitudinal studies report that hopelessness results in
elevated cortisol and immunosuppression in the general population and
HIV-positive individuals (Breier et al., 1987; Croes, Merz, & Netter, 1993;
Dickerson & Kemeny, 2004; Ironson, Balbin, et al., 2005; Udelman & Udelman,
1985). Specifically, reports indicate that hopelessness is associated with the
onset of HIV-related symptoms (Reed, Kemeny, Taylor, & Visscher, 1999)
and shorter survival time (Reed, Kemeny, Taylor, Wang, & Visscher, 1994).
Ironson, O’Cleirigh, et al. (2005) found that depression and hopelessness
were highly correlated and predicted viral load slope over a 2-year period
among HIV-positive individuals. Evidence for the interrelationships between
depression, hopelessness, and HIV progression is also seen in research dem-
onstrating that optimism is associated with later symptom onset (Reed et al.,
1999), slower immune decline (Ironson, Balbin, et al., 2005), and longer
survival time with AIDS (Reed et al., 1994). Although it is plausible that the
association between hopelessness and disease progression is mediated by
elevated cortisol, this relationship remains untested among HIV-positive
individuals.
Hopelessness may influence immune functioning indirectly, by encouraging
negative health behaviors. Consumed by a lack of hope, individuals are less
likely to plan or care about the future, which may result in substance abuse
(Bolland, 2003), loss of social support (Kashani, Canfield, Borduin, Soltys,

& Reid, 1994; Kashani, Suarez, Allan, & Reid, 1997), and medication nonad-
herence. In sum, in addition to influencing depression and physiological fac-
tors, the intermediary variable of hopelessness is linked to behaviors that
directly affect HIV progression.
Summary on Intermediary Factors

Linked With Elevated Cortisol Levels
We have discussed intermediary factors that act by elevating cortisol levels to
explain the relationship between depression and HIV progression. In particu-
lar, substance use, poor social support, and hopelessness are associated with
both depression and immunosuppression among HIV-positive individuals. In
addition, research suggests that these intermediary factors lead to a compro-
mised immune response through the mechanism of enhanced cortisol secre-
tion. Elevated cortisol, in turn, compromises the immune response, increasing
secondary diseases and speeding the progression to AIDS. Taken together, there
is preliminary support for multiple mediational pathways through which depres-
sion leads to substance use, poor social support, and hopelessness, which in
turn lead to elevated cortisol levels, and subsequently, to the worsening of
HIV. However, it is important to note that substance use, poor social sup-
port, and hopelessness are all intercorrelated (as they are with other behav-
ioral factors), providing potential secondary pathways to HIV progression.
Additional Intermediary Factors

Not Involving Elevated Cortisol
Depression → Medication
Nonadherence → HIV Progression
Research indicates depression to be a significant impediment to antiretroviral
medication adherence in clinical and community samples (Catz et al., 2000;
Gordillo et al., 1999; Kleeberger et al., 2001; N. Singh et al., 1996; Starace
et al., 2002). Lower adherence rates result in health complications, medication-
resistant HIV strains, and earlier death (Catz et al., 2000; Gifford et al., 2000;
Schneiderman, Antoni, Saab, & Ironson, 2001). For example, Perry and Karasic
(2002) demonstrated that moderate to severe depression is associated with poor
adherence to HAART, resulting in a 2.5-fold increase in risk of death. Focusing
on HIV-positive drug users, Waldrop-Valverde and Valverde (2005) found that
depression predicted nonadherence more than other types of psychologi-
Schuster et al. 131
cal distress. Sledjeski, Delahanty, and Bogart (2005) investigated the impact
of depression and posttraumatic stress disorder on antiretroviral medication
adherence. Participants with severe depression had lower adherence rates than
participants with other psychopathology. Finally, a multisite trial found that
the use of mental health services increased the probability of HAART adher-
ence among depressed HIV-positive individuals (Cook et al., 2006).
The relationship between depression and medication nonadherence is also
mediated through a number of indirect pathways. For instance, several studies
of HIV-positive individuals found three-way associations between depression,
medication nonadherence, and (a) substance use (Arnsten et al., 2002; Avants,
Margolin, Warburton, Hawkins, & Shi, 2001; Cook et al., 2007; Waldrop-
Valverde & Valverde, 2005), (b) social support (Catz, McClure, Jones, &
Brantley, 1999; Simoni et al., 2006), (c) hopelessness (Ironson, O’Cleirigh,
et al., 2005; N. Singh et al., 1999), and (d) general memory deficits (Ammassari
et al., 2004). In sum, depression renders medication compliance more challeng-
ing both directly and through secondary pathways.
Depression → Sexual Risk Behavior → Contraction

of Secondary Infections → HIV Progression
Theoretical and empirical studies have found that negative affect disturbs self-
regulatory processes, inhibiting cognitive reasoning and behavior control
(Gold & Skinner, 1992; Leith & Baumeister, 1996; Morris & Reilly, 1987).
Research suggests that depressive symptomatology in the general population
is associated with high-risk sexual behavior (Lehrer, Shrier, Gortmaker, &
Buka, 2006; Mazzaferro et al., 2006; Orr, Celantano, Santelli, & Burwell,
1994; Seth, Raiji, DiClemente, Wingood, & Rose, 2009). Among HIV-
positive individuals, depression is linked to risky sexual practices such as
unprotected anal and vaginal intercourse and sex with multiple partners (Kelly
et al., 1993; Kennedy et al., 1993; Murphy et al., 2001; Thompson, Nanni, &
Levine, 1996). Marks, Bingman, and Duval (1998) found that among HIV-
positive men, negative affect correlated with unprotected anal intercourse dur-
ing their most recent sexual encounter. In a different HIV-positive sample,
depression was correlated with trading sex for money or drugs, having sex
while high on drugs, and having more lifetime sex partners (Hutton, Lyketsos,
Zenilman, Thompson, & Erbelding, 2004).
Unsafe sexual behavior among HIV-positive individuals increases the risk
of the infected individual contracting other sexually transmitted viruses such
as syphilis, gonorrhea, Hepatitis B, and Hepatitis C, as well as secondary strains
of HIV. Such infections often lead to a more rapid disease progression among
preexisting cases of HIV (Blazquez, Madueno, Jurado, Fernandez-Areas, &

Munoz, 1995; S. Singh, Thappa, Jaisankar, & Sujatha, 2000).
The association between depression and risky sex among HIV-positive
individuals may be mediated by other factors such as feelings of hopelessness
and pessimism (Kalichman & Rompa, 2003; Rohde, Noell, Ochs, & Seeley,
2001). HIV-seropositive men who engage in unprotected anal intercourse fre-
quently believe that they have nothing left to lose (Gold, Skinner, & Ross,
1994). Depression also has a well-established link to increased substance use
(Armstrong & Costello, 2002; Upadhyaya, Deas, Brady, & Kruesi, 2002).
Substance abuse, in turn, is linked to risky sexual behaviors (Flom et al., 2001;
Latkin, Curry, Hua, & Davey, 2007; Robertson & Plant, 1988; Weeks, Grier,
Romero-Daza, Puglisi-Vasquez, & Singer, 1998). In sum, depression among
HIV-positive individuals is directly and indirectly associated with sexual
risk-taking, which renders at-risk individuals vulnerable to contraction of
additional infections that expedite immune system decline.
Summary of Additional Intermediary

Factors Not Involving Elevated Cortisol
To summarize, we discuss two behavioral factors that link depression with
compromised immune functioning over time, independent of cortisol secre-
tion: medication nonadherence and sexual risk-taking. Beyond univariate
relationships, medication nonadherence and sexual risk-taking may mediate
the relationship between depression and HIV progression, such that depres-
sion lowers medication adherence and increases sexual risk-taking behavior,
which (directly and/or indirectly) are associated with immune system decline.
However, beyond the proposed mediational pathways, current research sug-
gests that there may be secondary pathways, such that the relationship between
depression and medication nonadherence and sexual risk-taking is mediated by
lifestyle or emotional problems (e.g., hopelessness, substance use).
Conclusions, Limitations of the Current

Model, and Future Directions
Conclusions
It is reasonable to propose a model in which existing depression among HIV-
positive individuals leads to chronic cortisol elevations (Figure 1). This process
inhibits the release of interleukins and interferons, reduces the responsiveness
of lymphocytes (T cells) to infection, and damages or destroys lymphocytes.
Schuster et al. 133
Figure 1. Theoretical model outlining direct and indirect pathways to HIV

progression
Beyond this direct physiological effect, research suggests indirect pathways

from depression to immune system decline. It is hypothesized that depression is
associated with a variety of behavioral and psychological factors, such as sub-
stance use, poor social support, and hopelessness, which are associated with
increased cortisol secretion. Each factor is independently associated with
increased cortisol secretion, and likely mediates the relationship between
depression and HIV progression, although future studies should focus on estab-
lishing these mediational pathways directly.
In addition, there are two behavioral factors that exert influence on immu-
nofunctioning independent of elevated cortisol levels. In particular, depres-
sion is associated with poor medication adherence. This frequently results in
medication-resistant strains of HIV, declining CD4 counts, and increased
viral loads. In addition, depression increases the probability of engaging in
risky sex, which in turn increases the chances of contracting additional diseases
that compromise immune functioning.
As previously noted, many of our proposed mediators are intercorrelated.
As such, it is important to also consider secondary mediational pathways.
For instance, the pathways between depression and medication adherence and
sexual risk-taking might be mediated by substance use, whereas the pathway
between depression and substance use may be mediated by hopelessness.
Although a review of these secondary paths was beyond the scope of this
article, they are important to elucidate in future research.
Theoretical Considerations of the Current

Model and Future Directions
Several limitations apply to this conceptual model. First, the model is based
on reports of univariate, sometimes three- or four-way associations. A few
studies have used structural equation modeling to examine pathways and
interconnections among multiple variables. A true test of the proposed model
would require an examination of all paths simultaneously. Future research
could use mediational or structural modeling procedures to test parts of the
model, or the model in its entirety.
A second limitation is the small number of proposed mechanisms in the
relationship between depression and HIV progression. Among factors not
considered are other psychiatric conditions such as posttraumatic stress dis-
order or protective elements such as an adaptive coping style. Whether such
factors influence the relationship between depression, HIV progression, and
any of the intermediary variables remains unknown at this point.
A third limitation is that the current review focuses on only one physiolog-
ical factor, elevated levels of cortisol, ignoring other possible neuroendocrine
factors such as norepinephrine, DHEA, and neuropeptide substance P. Each
of these variables is associated with both depression and HIV progression
(Leserman, 2003). Although few studies have linked these physiological
variables to the behavioral, social, and environmental intermediary variables
discussed, future investigations of the proposed model should examine hor-
monal factors beyond cortisol.
Finally, although the model implies unidirectional relationships, many of
these relationships are in fact bidirectional (e.g., social support and depression).
Because statistical models do not determine directionality, and few HIV-related
studies have used stringent longitudinal methodology to determine bidirec-
tional relationships, it is impossible to know the impact of such relationships
on the proposed model. Future longitudinal research could investigate issues
such as how fluctuating depression levels affect social support status, sub-
stance use, or progression to AIDS in this high-risk population, and how these
factors in turn influence levels of depression. The ultimate goal would be to
develop more effective and holistic interventions to treat the multiple com-
plexities associated with HIV in the 21st century.
Schuster et al. 135
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interests with respect to the research,
authorship, and/or the publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or pub-
lication of this article.
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Bios
Randi Schuster is a postmaster’s doctoral student in clinical psychology at the
University of Illinois at Chicago.
Marina Bornovalova is an assistant professor and based out of the psychology

department at the University of South Florida.
Elizabeth Hunt is a doctoral student and based out of the psychology department at
the University of South Florida.

The Influence of Depression On The Progression of HIV: Direct and Indirect Effects

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425231

5231Schuster et al.Behavior Modification

The Influence 36(2) 123­–145

of HIV: Direct and

Randi Schuster1, Marina Bornovalova2,

jeopardize optimal treatment effect. Longitudinal studies suggest that chronic

Direct Consequences of Depression:

physiological mechanisms through which stress, including depression, leads to

Intermediary Factors Directly or Indirectly

Hepatitis B (Page-Shafer, Delorenze, Satariano, & Winkelstein, 1996). This results

Depression → Poor Social Support →HIV Progression

Depression → Hopelessness → HIV Progression

(Bolland, 2003), loss of social support (Kashani, Canfield, Borduin, Soltys,

Summary on Intermediary Factors

Additional Intermediary Factors

Depression → Sexual Risk Behavior → Contraction

preexisting cases of HIV (Blazquez, Madueno, Jurado, Fernandez-Areas, &

Summary of Additional Intermediary

Conclusions, Limitations of the Current

Figure 1. Theoretical model outlining direct and indirect pathways to HIV

Beyond this direct physiological effect, research suggests indirect pathways

Theoretical Considerations of the Current

Declaration of Conflicting Interests

infection. Journal of Acquired Immune Deficiency Syndrome and Human Retro-

Marina Bornovalova is an assistant professor and based out of the psychology

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The Influence 36(2) 123–145